The transforming growth factor-.beta.(TGF-.beta.) family of proteins consists of a number of related, but functionally distinct, proteins (Barnard, J. A. et al. (1990) Biochim. Biophys. Acta. 1032:79-87; Roberts, A. B. and Sporn, M. B. eds. The Transforming Growth Factor-.beta.s in Peptide Growth Factors and Their Receptors. I. Handbook of Experimental Pharmacology, vol. 95/I (Springer-Verlag, Berlin, 1990) 419-472). One member of the TGF-.beta. family of proteins, TGF-.beta.1, is a multifunctional cytokine with both growth promoting and inhibiting activities. Recently, TGF-.beta.1 has been found to play a role in modulating repair of vascular injuries such as restenosis lesions (Nikol, S. et al. (1992) J. Clin. Invest. 90:1582-1592) and atherosclerotic plaques (Kojima, S. et al. (1991) J. Cell Biol. 113(6):1439-1445.
Members of the TGF-.beta. family of proteins initiate cell signaling by binding to heteromeric receptor complexes of type I (T.beta.RI) and type II (T.beta.RII) serine/threonine kinase receptors (reviewed by Massague, J. et al. (1994) Trends Cell Biol. 4:172-178; Miyazono, K. et al. (1994) Adv. Immunol. 55:181-220). Activation of this heteromeric receptor complex occurs when TGF-.beta. binds to T.beta.RII, which then recruits and phosphorylates T.beta.RI. Activated T.beta.RI then propagates the signal to downstream targets (Chen, F. and Weinberg, R. A. (1995) PNAS92:1565-1569; Wrana, J. L. et al. (1994) Nature 370:341-347).
Until recently, the proteins involved in the intracellular TGF-.beta.signaling pathway were largely unknown. In 1995, however, a protein from Drosophila melanogaster, named Mothers against dpp ("MAD"), was cloned and found to be required for cell signaling by the TGF-.beta. family member decapentaplegic (dpp) (Sekelsky, J. J. et al. (1995) Genetics 139:1347-1358). Subsequently, cDNAs for four human homologues of the MAD protein, named hMAD1-4 and now generally known as MAD-related (MADR) proteins, were isolated and at least two of which (hMAD-3 and hMAD-4) were characterized as effectors of TGF-.beta. cellular responses (Zhang, Y. et al. (1996) Nature 383:168-172). hMAD-1 corresponds to MADR1, a tumor suppressor, whose inactivation may play a role in colorectal cancer (Eppert, K. et al. (1996) Cell 86:543-552). hMAD-4 is identical to DPC4, a candidate tumor suppressor, whose inactivation may play a role in pancreatic and other human cancers (Hahn, S. A. et al. (1996) Science 271:350-353). Once a cell is activated by a member of the TGF-.beta. family of proteins, activated MADR proteins or complexes of MADR proteins may be translocated into the nucleus to function as a transcriptional activator(s). Thus, as members of the TGF-.beta. family initiate a variety of beneficial effects on various cell types, e.g., epithelial cells and endothelial cells, it is desirable to modulate TGF-.beta. effects on such cells. One method of modulating TGF-.beta. initiated cell function is to modulate the function of proteins, such as the MADR proteins, which are involved in propagating the TGF-.beta. signal in the cell.